Recent findings have implicated changes in the status of myo-inositol and inositol-containing lipids, for which a role in nerve impulse conduction has long been suspected, in the onset of diabetic neuropathy. We have detected in vitro a specific and substantial increase in the turnover of triphosphoinositide (TPI) as measured by 32P incorporation in sciatic nerve from rats with chronic streptozotocin diabetes and which also manifest decreased peripheral nerve conduction velocities. We wish to investigate the hypothesis that this metabolic change is intimately related to development of abnormal peripheral nerve function. To do this we will: 1) characterize further the alterations in diabetic nerve phospholipid metabolism with respect to incorporation of several lipid precursors, and determine the minimum dose of streptozotocin and the minimum time after its administration needed for metabolic changes to appear. 2) attempt to prevent, ameliorate or reverse the change by feeding a diet enriched in myo-inositol and by insulin administration 3) evaluate the extent to which the metabolic alterations can be correlated with conduction velocities and morphometric changes in both streptozotocin diabetes and acute hyperosmolar hyperglycemia. 4) ascertain whether the affected TPI metabolic compartment is associated with the myelin or with non-myelin structures by means of subcellular fractionation of sciatic nerve and incorporation experiments using normal and diabetic vagus nerve as an example of a poorly myelinated nerve. 5) determine whether the consequences of diabetes in another animal model, the genetically diabetic mouse (C57BL/ks(db/db), give rise to similar correlated changes in sciatic nerve phospholipid metabolism and conduction velocity reductions. 6) investigate whether increased TPI turnover can be ascribed to a specific abnormality in phosphoinositide metabolism. Evidence for the mechanism responsible will be sought by quantification of phosphoinositides and related inositol phosphates, by pulse-chase experiments and by assay of pertinent enzymes which metablize phosphoinositides. The basic knowledge generated in this research will contribute useful information concerning experimental diabetic neuropathy in the animal models and may aid in understanding the origins and fundamental pathology of the human disease.